The investigation of human hemopoietic stem cells (HSC) has been hindered by the lack of suitable small animal models. We have recently addressed this deficiency by utilizing genetically altered strains of scid mice to develop a small animal model of human hemopoiesis. This model will now be used to determine the role of murine host genes on human HSC engraftment and the in vivo competitive repopulation of different human stem cell populations. To accomplish these goals, we propose an integrated approach involving 2 laboratories with expertise in mammalian genetics and in the development and characterization of small animal models of human cell engraftment. Specific Aim number 1 will utilize classical mammalian genetics in combination with transgenic and knockout technology to develop improved immunodeficient mouse recipients for human HSC engraftment. We have already shown that the genetic background of the NOD-scid mouse with defects in innate immunity allows a 5-10-fold increase in engraftment of human cord blood cells over that of C.B-17-scid mice. In Preliminary Studies we have documented that NOD-scid-beta2m0/0 mice engraft at higher levels with human stem cells than do NOD-scid mice, and that NOD-rag-10/0 mice engraft with human peripheral blood cells at levels comparable to that of NOD-scid mice. We will improve this model system by generating new transgenic and knockout immunodeficient NOD mice. Specific Aim number 2 will test these new genetic stocks of mice to identify the optimal host for human HSC engraftment. A novel competitive repopulation assay will be used to quantify the competitive engraftment of two or more human stem cell populations obtained from different individuals simultaneously in a single scid mouse. The development and validation of a small animal model of human hemopoiesis should also allow rapid evaluation and application of advances in gene therapy, and be important for designing treatment for hemopoietic disorders, AIDS, and other diseases.